bioartificial organs as outcomes of tissue engineering scientific and regulatory issues

Bioartificial Organs as Outcomes of Tissue Engineering

Scientific and Regulatory Issues

KIKI B. HELLMAN United States Food and Drug Administration

5600 Fishers Lane Rockville, Maryland 20852

On behalf of the U.S. Food and Drug Administration (FDA), it is a pleasure to participate in the International Conference on Bioart@cial Organs: Science and Technology, sponsored by the Engineering Foundation, and to participate in the continuing initiatives for fostering dialogue and cooperation between the public and private sector, academe, governments, and industry, both nationally and interna- tionally, in the development of novel technology(ies) and its promising contributions to clinical medicine.

From the FDA perspective, the conference is representative of endeavors to continually review the research advances in multi-disciplinary technologies and their applications to product development. It is indicative of the many efforts that the FDA has participated in over the last several years in the general area of biotechnology, its application to biomaterials, and novel cell and tissue engineering approaches.

In order to focus on those areas of benefit to the scientific community and to the continued progress in development of bioartificial organs, this communication considers the following topics:

advances in cell and tissue engineering responsible for major contributions to the field; scientific and regulatory issues integral to the translation of technology to products; and future challenges for the scientific and regulatory communities which are important for shepherding the field towards realization of its full potential in the armamentarium of clinical medicine.

ADVANCES IN CELL AND TISSUE ENGINEERING

The advances in cell and tissue engineering, and what they encompass, are major contributors that have led to the development of bioartificial organs as potential approaches for ameliorating different medical conditions. Cell and tissue engineering have emerged over the past ten to fifteen years as novel technologies that use the concepts and tools of biotechnology, molecular and cell biology, materials science, and engineering to understand the structure-function relationships in mam- malian tissues’ and to develop biological substitutes for the repair, reconstruction, regeneration, or replacement of tissue or organ functiom2

1

2 ANNALS NEW YORK ACADEMY OF SCIENCES

There are many avenues to reach the desired endpoint, as shown in FIGURE 1, which represents the universe of organ, cell, and tissue engineering applications as medical therapy alternatives. It can be conceived of as a continuum with regard to: 1) the initial source, either cells, tissues, or organs; 2) the level of processing, from minimally processed to modification of structure andor function; and 3) the end use as a direct implant or incorporation into a device for implantation or use extracorporeally .

As a source of products or systems, cell and tissue engineering technologies have emerged at the interface between the medical devices and biotechnology indu~tries.~ As bioartificial organs, these biological substitutes generally consist of cells or tissues and biomaterials. The biological component can be either metabolic or non-metabolic and can consist of cells or tissues from either human or animal sources that are isolated, native material or genetically manipulated. Cellular products such as cytokines, and cellular components, such as genes or structural elements, can be used either alone or in conjunction with cells or tissues. The biomaterial component of this biological substitute can consist of natural materials from native body tissues or synthetic materials designed for specific physical or chemical proper- ties. The biomaterial provides the: 1) scaffolding or three-dimensional architecture for tissue regeneration; 2) modulation of a specific cell function; or 3) immunopro- tection.

The general development of cell and tissue engineering and of bioartificial organs as outcomes or products of this technology is a result of three critical elements: 1) the progress in cell and tissue culture technology; 2) developments in biomaterials; and 3) the contributions of interdisciplinary research teams in academe and industry.

I Source j Processing I Use

I i Tissue +Dissociation

I

I

j i I

extracorporeal device

FIGURE 1. Engineering organs, cells, and tissues as medical therapy alternatives. (Modified from Berthiaume et al.")

HELLMAN: TISSUE ENGINEERING 3

TABLE 1. Key Developments in Cell and Tissue Culture Technology: Application to Bioartificial Organs

Cell growthhegeneration studies Cell structure/function modification - Surface receptors - Genetic manipulation

- Many organ system sites (skin, bone, cartilage, pancreatic islets, etc.) - Different host sources (autologous, allogeneic, xenogeneic)

Propagation of differentiated cells, tissues, and organs with desired function from:

CeWtissue growth scale-up in containers for direct clinical application (e.g., biosynthetic

Progress in stem cell research Skin)

PROGRESS IN CELL AND TISSUE CULTURE TECHNOLOGY

The ability to propagate differentiated cells, tissues, and organs with the desired function from many organ system sites, different host sources, and even in closed system containers for direct clinical application, such as biosynthetic skin, is due to the continued progress in cell and tissue culture technology over the last forty years and certain key developments (TABLE 1). These include: propagation of cells in uitro indefinitely in continuous culture and under conditions of a steady state as in a bioreactor, to preserve the cells or maintain the lineage, that is, genotype and phenotype; and modification of the cells’ structure or function in order to optimize a certain response via effects on cell surface receptors or manipulation of the genotype, andor via isolated and characterized cytokines, growth factors, and other agents. In addition, the progress being made in stem cell research, such as that in bone marrow cells, will expand to other areas, thereby permitting the culture of pluripotent cells that can be either used for repopulation or manipulated to permit propagation of the desired state of differentiation.

DEVELOPMENTS IN BIOMATERIALS RESEARCH

Owing to the progress made in biomaterials research over the last several years, it is now possible to use either synthetic or naturally derived materials tailored to the specific needs of the system. New materials andor applications are continually being developed.

Pivotal developments include the modification of materials’ surfaces to promote cell adhesion, and the use of resorbable materials that degrade when they are no longer needed, or materials that serve as scaffolding that enables cells to conform to a certain desired shape. The development of biomaterials that serve as membranes of selective permeability for use in cellular implants or extracorporeal systems has been critically important to the development of bioartificial organs. In addition, growth factors and other agents can be used in the system to mod@ the materials’ response, while nano-microfabrication technology enables the design of implants on the same level as that of the cells, permitting cells to communicate with each other and their environment. Further, self-assembly systems based on natural molecular self-assembly show promise for drughaccine delivery and, eventually, the delivery of gene or cell therapy (TABLE 2).


TABLE 2 Pivotal Developments in Biomaterials Research Modification of material surfaces to promote cell adhesion (e.g., RGD sequence) Bioresorbable materials Scaffolds to control cell regeneration in a certain shape Encapsulation technology applied to cellular implants (e.g., pancreatic islets, adrenal chromafh cells) and extracorporeal systems (ELADs) Response modifiers (e.g., growth factordother agents) Nano/microfabrication technology permits implant design on same level as cells and op-

Self-assembly systems via natural molecular self assembly (e.g., for drug/vaccine de- eration of cell recognition phenomena

livery)

PRODUCT APPLICATIONS

Just as the investment in basic research in molecular biology from the 1950s spawned biotechnology and its products in the 1980s, so has the research investment in cell biology, materials science, engineering and related fields been responsible for the development of cell and tissue engineered products such as bioartilicial organs. The interdisciplinary research teams composed of basic scientists, engineers, surgeons, and clinicians have been responsible for the cross-fertilization of ideas and approaches that have contributed to the field’s success and future promise.

There are many types of products and systems in different stages of development which promise major advances in clinical medicine. The opportunities/applictions in medical therapy range from: wound covering and repair systems, such as biosynthetic skin; bone, cartilage, ligament and tendon repair systems; and encapsulated cells for restoration of tissue and organ function, used either as implants, that is, secretory tissue “organoids” or ex uiuo, as metabolic support systems; to blood substitutes, such as liposome encapsulated hemoglobin; cardiovascular products, such as replacement heart valves, and endothelialized scaffolds for vascular grafts; human tissue products used either for direct replacement or in sites other than the retrieval site; nerve regeneration approaches; genitourinary products, such as artificial kidney; gene therapy vehicles; and drug delivery systems (TABLE 3). In point of fact, technology is under development to address pathology(ies) of virtually every organ system, owing to the establishment of productive research teams that are foci of imaginative approaches and industries endeavoring to translate the research into medical products and systems.

These initiatives are indicative of the novel therapeutic approaches that are being developed through technological advances that combine the delivery of phar- macologically active substances, elements of medical devices, biological products, and surgical interventiom3

SCIENTIFIC AND REGULATORY ISSUES

Cell and tissue engineered products, such as bioartilicial organs, are subject to regulatory evaluation by the national agencies responsible for overseeing their approval for commercial distribution and use. Issues of product safety and efficacy as they relate to product manufacture, preclinical evaluation, clinical investigation, and post-market requirements are considered in this evaluation.


FDA InterCenter Tissue Engineering Working Group

The FDA InterCenter Tissue Engineering Working Group (TEWG) was established approximately three years ago to address the scientific and regulatory issues of cell and tissue engineered products. The Working Group has accomplished a great deal in a relatively short time; it has facilitated communication, enhanced cooperation, and promoted regulatory harmonization across the Centers of the Agency, with other national regulatory bodies, and with the research and development community to shepherd the technology and its products.

To accomplish its goals, the Working Group has developed a number of ongoing projects in key areas. These include efforts in: information updates and technology monitoring via the FDA Tissue Engineering Knowledge Base (TED) and publications on generic product and review issues; training and education through courses coordinated by the FDA Staff Colleges, and conferenceslworkshops organized towards specific goals such as the May 1996 Toronto Workshop on global regulatory perspectives for tissue engineered products; and a science-based rationale (SBR) for regulatory decision making (TABLE 4). The SBR effort is interacting with the voluntary guidance initiative of the Tissue Engineering Special Interest Group of the Society for Biomaterials and complements efforts discussed by the representatives at the Toronto Workshop, i.e., Australia, Canada, the European Union, Japan, and the United States.

Taken together, these efforts are pivotal in developing a proper regulatory approach. As these products assume a worldwide marketplace, assurance of consistent regulatory procedures among different countries for their evaluation becomes more important, and a common regulatory approach is critical for reaping the public health benefits worldwide. To this end, an understanding of how the products are

TABLE 3. Cell and Tissue Engineering; Applications in Medical Therapy Biological and interactive dressings in wound healing

Bone, cartilage, ligamenthendon repair systems 0 Encapsulated cells for restoration of tissue and organ function

Wound covering and repair systems

- In vitro: secretory tissue “organoids” - Bioartificial pancreas - Neurodegenerative disease (Parkinsons)

- Bioartificial liver - Ex viuo: metabolic support systems

Blood substitutes - Liposome encapsulated hemoglobin Cardiovascular tissue engineered devices - Replacement heart valves - Endothelialized scaffolds for vascular grafts Human tissue products - Direct replacement

- Use in sites other than retrieval site - Heart valves, corneas

- Small bone fragments Nerve regeneration approaches Genitourinary tissue engineered products

Gene therapy vehicles Drug delivery systems

- Artificial kidney


TABLE 4. FDA Intercenter Tissue Engineering Working Group (TEWG): Ongoing Projects

Information Updatesmechnology Monitoring FDA TE Knowledge Base (TEKB) Publications on generic tissue engineering product, review issues

FDA Staff Colleges ConferenceslWorkshops

Interaction with Voluntary Guidance Initiatives

Outcome of May 1996 Toronto Workshop between Australia, Canada, European

Training and Education

Science-based Rationale (SBR) for Regulatory Decision Making

International Regulatory Perspective for Tissue Engineered Products

Union, Japan, United States

Information sharing (databases) Research Workshops/Courses Guidance

Cooperative Projects with PublidPrivate Groups

regulated, who regulates them, the pre- and post-market requirements, and most importantly, the rationale for decision making are critical for the ultimate development of a global regulatory perspective for establishing the consistent quality of present and future products. Cooperative projects with public and private groups, such as the National Institute for Standards and Technology (NIST), the Pittsburgh and Toronto Tissue Engineering Initiatives, and others in information sharing, research, especially test method development and generic research in enabling technologies, workshops, and guidance for the industry exemplify the importance of a working interchange among all partners of the enterprise devoted to the safe and efficacious application of cell and tissue engineering technology to medical products.

Product Safety and Effectiveness

An important goal of the Working Group is to identify generic safety and effectiveness issues for consideration by the community in its development of products. Examples of these issues are: product consistency and stability in manufacture, including material sourcing, adventitious agents, toxicity testing, and sterility for preclinical safety; material characterization, for example, structural and functional activity, biomaterial compatibility testing, and in uitro animal models for preclinical activity/evaluation; and clinical indications, endpoints for clinical efficacy, safety monitoring, and post-market reporting during clinical investigation (TABLE 5).

Combination Products and Regulation

Many tissue engineered products such as bioartificial organs are combination products in the regulatory sense, that is, they may constitute a combination of a drug, device, or biological product. The FDA Intercenter Agreements were established to clarify product jurisdictional issues for such combination products. The Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), and the Center for Drug Evaluation and Re-


search (CDER) have entered into these agreements, and there are guidance documents between the Centers that describe the allocation of responsibility for certain products and product classes. For example, tissues and tissue engineered products are under the regulatory purview of both the CBER and CDRH. Both Centers are involved in the evaluation of combination products, with the lead Center currently identilied by the primary mode of action of the combination product; the other Center acts as a consultant. This approach and others will be evaluated by the FDA Tissue Engineering Working Group as it develops the Science-Based Rationale (SBR) for Regulatory Decision Making.

Certain scientific issues have been identified as important in molecular and cell biology, and biornaterials for continued progress in cell and tissue engineering (TABLE 6). Doubtless, others would add to these lists; they are, by no means, exhaustive and, as is the nature of science, ever-changing.

In the area of molecular and cell biology, by far the most important issues are the control of cellular proliferation and differentiation and modulation for the desired cell function or phenotype, with the development of adequate test methods to monitor cellular activity. As systems are developed with more than one cell type, it will be important to understand how different cells communicate with one another, and how this can be optimized in the desired setting or environment. With the

TABLE 5. Regulatory Issues in Manufacture, Preclinical Evaluation, and Clinical Investigation for Cell and Tissue Engineered Products

Product consistency Product stability

Functional Genetic

Manufacture

Preclinical Safety Material sourcing Adventitious agents

Testing Process validation

Toxicity testing Short term Chroniclrepeated dose Carcinogenicity Immunogenicit y

Sterility Sterilization by-products

Material characterization structurallfunctional activity Preclinical Activity

Biological cellsltissues Biomaterial

Biomaterial compatibility testing In vitrolanimal models

Efficacy measures Clinical

Indications Efficacy endpoints Safety monitoring Population exposure Post-market reporting


increased use of allogeneic and xenogeneic cell and tissue sources comes the need to assure graft and host immunocompatibility, or ways to minimize or eliminate the host’s untoward immunological reaction or inflammatory response. In addition, it must be remembered that there may be subpopulations of individuals for which the cells or tissues may have altered safety, such as immunosuppressed individuals. If genetically modified cells are utilized, the potential for cell transformation by the vector, vector stability, optimal functioning of the inserted gene, as well as the inflammatory response at the implant site, which is a potential for all implants, must be considered.

For biomaterials, an important issue is whether a naturally derived or a synthetic material is the appropriate choice for a particular application. This will, to some extent, be determined by what the biomaterial is asked to do, that is, its function. Will it last indefinitely or will it degrade or resorb over a period of time? What structural or mechanical characteristics are needed for or dictated by the in situ environment?

It is important to minimize or eliminate reactions at the biomaterial-host interface, such as the potential for inflammation and biodegradation, and to identify and characterize the mechanisms of degradation and its byproducts. If a material is designed to biodegrade, it will be important to control and measure the rate of degradation. Will the material induce a fibrotic reaction in the host? How will the fibrotic potential be determined? Are there approaches for preventing fibrosis by testing the host material-product interface? Of course, some inflammation and fibrotic response accompany virtually any soft-tissue implant or surgical procedure. The important question is whether the intensity of the response represents a safety risk to the host or interferes with the product’s effectiveness. The host itself, and the individual variations in response, must also be considered. The functional activity of any product must be consistent and predictable from product to product. To that end, variation in a biomaterial must be minimized or eliminated by consistent processing methods and testing parameters.

TABLE 6. Scientific Issues for Bioartificial Organs as Outcomes of Cell Biology and Tissue Engineering MolecularlCeU Biology

Control of proliferatioddifferentiation Modulation of cell functiodphenotype Cell-cell communication Control of inflammatory response Control of immunological responses Genetically modified cells

Optimal gene function Vector stability

Biomaterials Natural versus synthetic materials Minimize/eliminate reactions at biomaterial-host interface

Potential for inRammation and/or biodegradation Control of fibrotic response Biomaterial stability

If biodegradable, control and measure rate of degradation Biomaterial reproducibility

Understand mechanisms of degradation and its by-products

Minimize and eliminate variation by consistent processing methodsltesting parameters


TABLE 7. Future Challenges for Bioartificial Organs ~~

Science Novel applications for reconstructive surgery Union of genetic techniques and tissue engineering Novel approaches for delivery of genekell therapy Development of functional artificial organs

Regulation Science-based rationale for decision making International regulatory perspective

FUTURE CHALLENGES

What are the future challenges for cell and tissue engineering and bioartificial organs from both the scientific and regulatory perspectives? Although any number of items could be identified, certain approaches, which build on the progress achieved and the successes, hold promise: novel applications for reconstructive surgery that utilize methods developed for biosynthetic skin; the union of genetic techniques with cell and tissue engineering; tissue engineered systems for the delivery of gene and somatic cell therapy; and the development of functional artificial organs, such as the artificial kidney (TABLE 7).

From the regulatory view, certainly a regulatory framework that utilizes a science-based rationale for regulatory decision making and an international regulatory perspective will contribute to establishing the proper niche for tissue engineered products and bioartificial organs in clinical medicine.

ACKNOWLEDGMENTS

The author wishes to thank the members of the Food and Drug Administration (FDA) Intercenter Tissue Engineering Working Group for their many contributions and suggestions, especially Drs. Grace Lee Picciolo, Charles Durfor, and Emma Knight.

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bioartificial organs as outcomes of tissue engineering scientific and regulatory issues

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